Currently drug therapy to profoundly alter the time course of insidious neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic, hearing loss related, and/or metabolic diseases towards early death is completely absent, therefore there is a unmet medical need. For instance, current recommendations from the NCL-Foundation due to the severity of the consequences of Batten Disease, is a palliative therapy started as early as possible. Epilepsy is treated with valproate and lamotrigine, spasms with baclofen and tetrazepam, and myoclonus epilepsy with piracetam and zonisamide (leaflet given out by NCL-Stiftung).
Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig's Disease) is a neurodegenerative disorder characterized by loss of neurons in the brain stem, cerebral cortex, and motor neurons of the spinal cord, that leads to progressive weakness and death within 3-5 years upon onset. For ALS, there have been a variety of treatments, and none have been proven effective to curb progression towards death, except riluzole. Riluzole extends life to a modest extent (several months) and extends the time before the patient needs ventilation support, but signs of liver toxicities (˜10%) must be monitored.
Alzheimer's Disease (AD), is a disorder characterized by loss of neurons in the brain corresponding to a decline in cognition and premature death. Despite that attempts of a host drug therapies, the drugs have failed to significantly alter lifespan of the patients. Parkinson's Disease, well known for its impact on Michael J. Fox, Mohamed Ali and others, is a slow killer of dopamine producing neurons called the dopaminergic neurons. Current therapies are focused on replacing dopamine and no new advancements have been made in quite a while.
Duchene Muscular Dystrophies (DMD), a pediatric neuromuscular disease in young boys (X-Chromosome), is an aggressive disorder such that the children are in leg braces at 8 years of age and in a wheel chair at 10. The loss of the dystrophin gene affects both the brain and muscle, the only two tissues in which it is expressed. The loss of dystrophin causes osmotic swelling of the mitochondria, bursting, and muscle wasting. Other forms of ataxia, and a host of other neurodegenerative/neuromuscular-degenerative diseases, have no treatments to profoundly alter the course of disease progression towards early death. Multiple sclerosis, is an autoimmune disorder of the CNS with no known etiology. Once disease onset occurs, the myelin sheaths (insulation surrounding nerve fibers or axons) are attacked by the immune cells, causing neuronal dysfunction between the brain and bodily organs. The results is a wide range of neurological symptoms such as involuntary movements of limbs that impair walking, visual/speech impairment, dysfunction of bladder and bowel, etc. Although lifespan is only moderately shortened, MS typically begins to manifest at the age of 20-30, with symptoms progressively getting worse over time. Currently, there are a host of drugs for immune suppression, however none are “disease-modifying” for treating MS, nor do any of the drugs protect against the disease progression.
In addition to neurodegenerative and autoimmune diseases, there is an unmet medical need for treatments of developmental diseases like Angelman Syndrome (AS), a pediatric neurodevelopmental disorder associated with developmental delay, motor dysfunction, lack of speech, and epilepsy caused by mutation in an imprinting gene called ubiquitin ligase E3A (UBE3A). Similarly, Rett Syndrome, is a pediatric degenerative disease that affects young girls (X-Chromosome, boys die in-utero) and leads to death. Currently there are no therapies to treat the effects of the disease that include respiratory issues, movement issues, seizures, etc.
In addition to the useful treatment of neurodegenerative, neuromuscular, autoimmune, and developmental diseases, the pandemic of metabolic diseases has very few drug therapy options that work to the root of the problem to resolve the effects of over-nutrition and subsequently obesity. Obesity is pandemic and intractable. There are approximately 1-billion over-weight adults worldwide, with over 300 million clinically obese. The US alone shows 35% of Americans with a BMI over 30 and 1 out of 400 with a BMI of 50 (˜800,000 individuals). Obesity can lead to ectopic lipid accumulation (e.g. nonalcoholic fatty liver disease, NAFLD) and oxidative damage from reactive oxygen species. As a result, obese individuals are at increased risk for numerous other diseases, including insulin resistance, sleep apnea, hypertension, kidney disease, inflammation, knee-joint complications, depression, high blood pressure, cardiovascular disease, Type-2 diabetes (T2D), and even some cancers. While even small amount (˜5%) of weight loss can yield metabolic benefits, it is difficult for most patients to achieve and sustain such weight loss. Thus, bariatric surgery is now touted as the best method to reverse obesity. Though increasingly popular, bariatric surgery often requires a permanent anatomical change to the gastrointestinal tract that essentially enforce reduced calorie intake. These procedures are associated with mortality ( 1/200) and short and long term morbidity such as wound complications and venous thrombosis as well as reactive hypoglycemia, micronutrient deficiency, dumping syndrome, etc. These procedures pose additional challenges in patients with extreme obesity (BMI>50 kg/m2). Pharmaceutical approaches to remedy obesity have focused on inducing malabsorption (e.g., orlistat) or satiety (e.g., rimonobant, sibutramine) but are minimally effective (˜5% body weight) and associated with significant adverse effects (e.g. steatorrhea, depression, and MI, respectively). New pharmacological therapies are needed.
Consequently, there is a profound need for improved treatments for neurodegenerative, neuromuscular, developmental, autoimmune and/or metabolic diseases.